ABSTRACT: To date age-related changes in bone are thought to result from two distinct and potentially synergistic causes: i) systemic hormonal changes, particularly somatopause, the age-related declines in growth hormone [GH] and its mediator insulin-like growth factor-1 [IGF-1] and ii) ?intrinsic? cumulative or temporal changes in bone cell activity and tissue properties. These processes are concomitant and overlapping, and their distinct effects on age-related bone loss were not established. We have developed an integrative molecular-to whole bone approach to study novel mechanisms controlling bone integrity during aging. We build on a long-standing collaboration between Dr. Schaffler, an expert in osteocytes and bone biomechanics, and Dr. Yakar, an expert in GH/IGF-1 physiology, and a new collaboration with Dr. Pavlov, an expert in mitochondria. We focus on osteocytes, which comprise > 95% of bone cells and are extremely long-lived. Osteocytes integrate the bone's hormonal and mechanical environment, produce the key signals that turn on osteoblasts and osteoclasts, and also directly influence bone material properties. In this proposal we will study the effects of the somatotropic axis on the viability and function of the aging osteocytes via the following aims: 1) Determine the cellular mechanisms by which GH/IGF-1 affect bone tissue quality; 2) Determine how GH/IGF-1 axis controls osteocyte viability and metabolic flexibility during aging. Our studies link three hallmarks of aging ?altered intercellular communication?, which is central to tissue integrity, ?mitochondrial dysfunction?, which is central to cell survival, and ?deregulated nutrient sensing?, which is central to cellular metabolism. We expect unraveling the distinct and overlapping effects of normal aging and somatopause specifically on bone health. Completion of our studies will determine the morphological and the molecular mechanisms by which the GH/IGF-1 axis affects osteocytes of the aging skeleton.